ABSTRACT Osteoporosis is a sex-dependent, metabolic disease characterized by decreased bone mineral density (BMD), deterioration of bone microstructure, and increased risk of fracture. BMD is a strong predictor of fracture and a highly heritable quantitative trait. In recent years, genome-wide association studies (GWASs) have identified dozens of loci influencing variation in BMD; however, few of the underlying genes have been identified. One reason that gene discovery has been limited is a lack of transcriptomic data on human bone cells and tissues that can be used to link GWAS variants to alterations in the expression of causal genes. Here, we address this deficiency by generating population-scale transcriptomic profiles on the three primary cell types involved in determining BMD levels: osteoblasts, osteoclasts and osteocytes. These data will be generated from bone and marrow samples collected from individuals undergoing hip replacement surgery. In the same cohort, we will generate co-relatable tissue-level (microarchitecture, mineralization, and biomechanical properties) and in vitro cellular phenotypes (osteoblast and osteoclast activities). In Aim 1, RNA-seq data and high-density genotypes will be used to identify expression quantitative trait loci (eQTL) that colocalize with BMD GWAS loci. In Aim 2, we will prioritize genes and determine the mechanisms through which they impact BMD through association with tissue-level and cellular phenotypes and the investigation of co-expression networks. Genes will also be tested for association with a nearly identical set of phenotypes in a large outbred mouse population. In Aim 3, we will determine if SPTBN1, a gene identified in preliminary studies, is causal for a BMD GWAS locus on Chr. 2p16.2, and one additional candidate identified via the studies of Aims 1 and 2 will be tested for an effect on BMD and other bone traits in vivo. Our novel and innovative approach for informing GWAS will identify genes responsible for GWAS loci and lead to the discovery of putative therapeutic targets for the prevention and treatment of bone fragility.